title: Beyond ubiquitination: the atypical functions of Fbxo7 and other F-box proteins.
abstract: F-box proteins (FBPs) are substrate-recruiting subunits of Skp1-cullin1-FBP (SCF)-type E3 ubiquitin ligases. To date, 69 FBPs have been identified in humans, but ubiquitinated substrates have only been identified for a few, with the majority of FBPs remaining 'orphans'. In recent years, a growing body of work has identified non-canonical, SCF-independent roles for about 12% of the human FBPs. These atypical FBPs affect processes as diverse as transcription, cell cycle regulation, mitochondrial dynamics and intracellular trafficking. Here, we provide a general review of FBPs, with a particular emphasis on these expanded functions. We review Fbxo7 as an exemplar of this special group as it has well-defined roles in both SCF and non-SCF complexes. We review its function as a cell cycle regulator, via its ability to stabilize p27 protein and Cdk6 complexes, and as a proteasome regulator, owing to its high affinity binding to PI31. We also highlight recent advances in our understanding of Fbxo7 function in Parkinson's disease, where it functions in the regulation of mitophagy with PINK1 and Parkin. We postulate that a few extraordinary FBPs act as platforms that seamlessly segue their canonical and non-canonical functions to integrate different cellular pathways and link their regulation.
authors.affiliation: Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK.
authors.forename: David E
authors.initials: DE
authors.lastname: Nelson
authors.forename: Suzanne J
authors.initials: SJ
authors.lastname: Randle
authors.forename: Heike
authors.initials: H
authors.lastname: Laman
mesh_terms: D000818:Animals; D002453:Cell Cycle; D051361:Cyclin-Dependent Kinase 6 / Q000378:metabolism; D019143:Evolution, Molecular; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D063306:Mitophagy; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics / Q000503:physiopathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism*; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination; D000099202:PTEN-Induced Putative Kinase
chemical_list: D051361:Cyclin-Dependent Kinase 6; D044783:F-Box Proteins; D046988:Proteasome Endopeptidase Complex; D011494:Protein Kinases; D011506:Proteins; D044843:SKP Cullin F-Box Protein Ligases; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C489149:FBXO7 protein, human; C121623:PSMF1 protein, human; C111567:parkin protein; C495911:CDK6 protein, human
keywords: E3 ligase; F-box protein; Fbxo7/PARK15; Parkinson's disease; mitophagy; ubiquitin